The development of multicellular organisms requires the orchestration of many precisely coordinated events involving cell-type specific growth, proliferation, differentiation, migration, and cell death. Not surprisingly, intercellular communication plays critical roles in these processes. Although the molecular mechanisms involved in this communication are in general poorly understood, this research field is characterized by increasingly rapid progress initiated by the realization that viral oncogenes are, in many cases, transformed versions of cellular genes (proto-oncogenes) that participate in the intercellular communication directing development. Furthermore, it has been established that many non-viral forms of cancer also result from transformation of genes involved in signal transduction (e.g. growth factors, growth factor receptors, and transcription factors).
A large number of mammalian growth factor receptors have been cloned and many are recognized proto-oncogenes (Yarden and Ullrich, 1988). Most of these cloned receptors are members of a superfamily of integral membrane proteins with intrinsic, growth factor-inducible, tyrosine kinase activity. An extensive research literature now documents the critical roles these receptors play in cell proliferation, differentiation, and malignant transformation. However, multiple lines of evidence suggest that members of the G-protein coupled receptor (GPR) superfamily may also participate in mammalian development and oncogenesis. For example, both the yeast S. cerevisiae and the slime mold D. discoideum express GPRs that regulate cell differentiation (Devreotes, 1989; Sprague, 1991). In addition, mammalian mitogenesis and cell proliferation are affected by several peptides and neurotransmitters which are known to interact with GPRs (Hanley, 1989; Zachary et al., 1987).
Perhaps the most direct evidence linking GPRs with ontogeny and cancer has been provided by the ectopic expression of GPRs in tissue culture cells. Thus, the mas oncogene encodes a putative GPR (p.sup.mas) and leads to malignant transformation when transfected into NIH3T3 mouse fibroblasts cells (Young et al., 1986). In addition, several serotonin and muscarinic acetylcholine receptors (all GPRs) also produce this malignant transformation if ectopically expressed in NIH3T3 cells and stimulated by their respective ligands (Gutkind et al., 1991; Julius et al., 1989; Julius et al., 1990). While these data illustrate that GPRs can greatly influence cell proliferation and morphology, the GPRs that were studied are unlikely to be involved in these processes in vivo because they reside in fully differentiated, postmitotic cells such as neurons where serotonergic receptors, muscarinic receptors, and most likely p.sup.mas regulate the changing electrical properties of neuronal membranes involved in neurotransmission. However, these data support the possibility that other GPRs are expressed in vivo in immature cells where they regulate proliferation and differentiation. Furthermore, these data suggest that some forms of cancer may result from mutations or viral infections that lead to improper functioning, activation, or expression of such GPRs. Thus, identification and characterization of such receptors should significantly advance both the study of normal development as well as the search for diagnostic and therapeutic tools in oncology.